Substituted cycloalkyl lactamimides

ABSTRACT

Compounds possessing hypoglycemic, hypotensive, antiinflammatory, anticoagulant and diuretic activity are represented by compounds of the following formula ##STR1## wherein Y is thienyl, cycloalkyl of from 5 to 7 carbon atoms, phenyl or substituted phenyl in which case the substituents on the substituted phenyl are selected from halogen, such as fluorine, chlorine, bromine or iodine, lower alkyl of from 1 to 4 carbon atoms and lower alkoxy of from 1 to 4 carbon atoms; Z is hydrogen or hydroxy; R is hydrogen, lower alkyl of from 1 to 4 carbon atoms, phenyl or benzyl; R 1  is hydrogen, lower alkyl of from 1 to 4 carbon atoms or halogen, such as chlorine, fluorine, bromine or iodine; m is from 3 to 6; and n is from 3 to 11. Pharmaceutical compositions of these compounds and their use are also disclosed.

This is a division of application Ser. No. 386,995, filed Aug. 9, 1973which is a continuation-in-part of application Ser. No. 143,259, filedMay 13, 1971, now abandoned.

FIELD OF INVENTION

This invention relates to novel substituted cycloalkyl lactamimidecompounds and pharmaceutical compositions thereof. More particularly,this invention relates to said novel compounds and compositions havinghypoglycemic utility and additionally, hypotensive, anticoagulant anddiuretic activity.

SUMMARY OF INVENTION

The novel compounds of this invention are represented by those havingthe following formula ##STR2## wherein Y is thienyl, cycloalkyl of from5 to 7 carbon atoms, phenyl or substituted phenyl in which case thesubstituents on the substituted phenyl are selected from halogen, suchas fluorine, chlorine, bromine or iodine, lower alkyl of from 1 to 4carbon atoms and lower alkoxy of from 1 to 4 carbon atoms; Z is hydrogenor hydroxy; R is hydrogen, lower alkyl of from 1 to 4 carbon atoms,phenyl or benzyl; R¹ is hydrogen, lower alkyl of from 1 to 4 carbonatoms or halogen, such as chlorine, fluorine, bromine or iodine; m isfrom 3 to 6; and n is from 3 to 11. Also included within the scope ofthe invention are the pharmaceutically acceptable acid addition salts ofthese compounds and the individual geometric and optical isomers whereapplicable. Pharmaceutical compositions of said novel compounds and theadministration of said compounds to a host for their biological activityare also included within the scope of the disclosed invention.

DISCUSSION OF PRIOR ART

The compounds of the present invention are novel compounds having one ormore biological activities rendering them useful in the pharmaceuticalarts. The closest prior art known to applicants is the compound1-methyl-2-[(trans-2-phenylcyclopropyl)imino]pyrrolidine disclosed inExample No. 10 of French Pat. No. 1,576,111 of McNeil Laboratoriespublished on July 25, 1969. The French patent relates only to a processfor the preparation of the aforementioned and related compounds anddiscloses no use for said compound.

DETAILED DESCRIPTION OF INVENTION

For convenience and uniformity we have represented and named allcompounds described in the disclosure as substituted2-iminoperhydroazacarbocyclics, as represented by Formula I. It isknown, however, that compounds of this type as acid addition salts mayalso be represented by the tautomeric form illustrated by the followingFormula II: ##STR3## This tautomerism has been discussed by R. Kwok andP. Pranc, J. Org. Chem. 32, 740 (1967). Structures of this formula couldbe named differently. In solution, under the conditions of thetherapeutic utility, the proportion of each tautomeric form, or thedelocalization of the charge between the two nitrogen atoms, will bedependent upon numerous factors including the nature of thesubstituents, the pH of the medium, and the like. This equilibrium stateis conveniently depicted by the following Formula III: ##STR4## It isunderstood that this disclosure relates to compounds represented ornamed in either tautomeric form.

Preferred compounds of this invention are compounds of the followingtype: ##STR5## wherein Y' is thienyl, cyclohexyl or phenyl, Z ishydrogen or hydroxy; m' is 3 to 5; and n' is 4 to 7.

As examples of the cycloalkyl radicals which the symbol Y may representin each of the above Formulas I, II or III there may be mentioned, forexample, cyclopentyl, cyclohexyl and cycloheptyl.

As examples of the lower alkyl radicals that R and R¹ may represent, aswell as the lower alkyl radicals which may appear as substituents on thesubstituted phenyl radicals that the symbol Y may represent there may bementioned, for example, methyl, ethyl, propyl and butyl. Likewise, asexamples of the lower alkoxy radicals which may appear as substituentson the substituted phenyl radicals that the symbol Y may represent theremay be mentioned, for example, methoxy, ethoxy, propoxy and butoxy.

As examples of compounds of this invention there may be mentioned, forexample,

hexahydro-2-[(trans-2-phenylcyclopentyl)imino]azepine hydrochloride,

2-[2-({p-chlorophenyl}cyclopentyl)imino]hexahydroazepine hydrochloride,

5-tert-butylhexahydro-2-[(cis-2-phenylcyclopentyl)imino]azepinehydrochloride,

hexahydro-2-[2({o-tolyl}cyclohexyl)imino]azepine hydrochloride,

and 2-[2-({m-anisyl}cyclohexyl)imino]hexahydroazepine hydrochloride.

As examples of preferred compounds of this invention there may bementioned, for example,

hexahydro-2-[(2-phenylcyclopentyl)imino]azepine hydrochloride,

hexahydro-2-[(2-phenylcycloheptyl)imino]azepine hydrochloride,

2-[(2-cyclohexylcyclopentyl)imino]hexahydroazepine hydrochloride, andmost preferably the cis isomer,

2-[(2-phenylcyclopentyl)imino]piperidine hydrochloride,octahydro-2-[(2-phenylcyclopentyl)imino]azonine hydrochloride,

hexahydro-2-[(2-{2-thienyl}cyclopentyl)imino]azepine hydrochloride,

2-[(2-cyclohexylcyclopentyl)imino]piperidine hydrochloride, and

2-(hexahydroazepin-2-ylidenamino)-1-phenylcyclopentanol hydrochloride.

Pharmaceutically acceptable acid addition salts of the base compounds ofthis invention are those of any suitable inorganic or organic acids.Suitable inorganic acids are, for example, hydrochloric, hydrobromic,sulfuric or phosphoric acids and the like. Suitable organic acids are,for example, carboxylic acids such as acetic, propionic, glycolic,lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, salicylic, 2-phenoxybenzoic and the like, or sulfonic acidssuch as methane sulfonic, 2-hydroxyethane sulfonic acid and the like.

It has been found that the novel compounds of this invention, includingacid addition salts and individual optical and geometric isomers whereapplicable, possess hypoglycemic utility. In addition to theirhypoglycemic utility these compounds also possess diuretic,anticoagulant and hypotensive activity. These compounds can be used inthe form of pharmaceutical preparations which contain the novelcompounds suitable for oral or parenteral administration. The quantityof compound in the unit dosage can vary over a wide range to providefrom about 1.0 mg/kg to about 100 mg/kg of body weight of the patientper dose to achieve the desired effect. The desired hypoglycemic effectcan be obtained, for example, in a 70 kg subject by consumption of 25 to500 mg of the active ingredient taken 1 to 4 times daily.

The utility of the compounds of this invention is illustrated by thefollowing. The compound of Example 3 demonstrated in vitro an 89%inhibition of adenosine diphosphate induced platelet aggregation inhuman platelet rich plasma when 100 μg of the compound was added to eachmilliliter of plasma. When 25 mg/kg of body weight of the compound ofExample 1 was orally administered to rats the percent of urine excretionmeasured in milliliters was increased by 118% in 5 hours over that of acontrol group. When the compound of Example 19 was orally administeredto rats at 100 mg/kg of body weight a 34% reduction in plasma glucosefrom control resulted. In a carrageenin abscess test when 500 mg/kg ofbody weight of the compound of Example 22 was orally administered torats there was a decrease in abscess weight by 60%.

The compounds of this invention are prepared by reacting an excess of alactim ether of the formula ##STR6## with a primary amine of thefollowing formula ##STR7## in a manner like that reported by R. E.Benson and T. L. Cairns, J. Am. Chem. Soc. 70, 2115-8 (1948). Thevarious symbols, that is, n, R¹, Y, Z and m have the meanings definedhereinbefore, and lower alkyl may be methyl, ethyl, or the like. Thisreaction may be carried out either in the presence or absence of asolvent. When a solvent is used it is preferred that a lower alcohol,such as, methanol, ethanol or the like be used; however, other solventssuch as benzene, toluene and the like may be used. A basic or acidiccatalyst such as a tertiary amine or hydrogen chloride may be added tothe reaction mixture. In general it is preferred that the hydrochloridesalt of the amine be used in the reaction. The temperature of thereaction can vary from -40° C. to 180° C., and the preferred temperatureis about 15° to about 25° C. The reaction time varies from about 1 hourto about 60 days being dependent upon the temperature of the reaction,the reactant primary amine, and more particularly, on the degree ofstearic hindrance of the amine since highly stearically hindered aminesreact very slowly.

The lactim ethers which find use in this reaction may be prepared fromcommercially available corresponding lactams by methods known in theart. For example, by reaction of an appropriate lactam with dimethylsulfate in a solvent such as benzene, toluene, xylene or the like at thereflux temperature of the solvent for 2 to 24 hours the correspondingO-methyl lactim ether is obtained.

The amines which find use in this invention may be prepared by severalknown methods. The substituted cycloalkylamine may be obtained from thecorresponding nitro derivative or the oxime [C. Kaiser et al., J. Med.Pharm. Chem. 5, 1243 (1962)] by reduction. Or, thecyclohexylcycloalkylamine compounds may be obtained by hydrogenation ofthe corresponding phenylcycloalkylamine derivative. Also by the Leuckartreaction the appropriately substituted cycloalkanone is heated withammonium formate to a temperature of 180° to 200° C. for 2 to 12 hoursto give the desired substituted cycloalkyl amine. The substitutedcycloalkanone derivatives may be obtained by a Grignard reaction of asuitable aryl- or cycloalkylmagnesium halide with an appropriatecycloalkanone to give the corresponding substituted cycloalkalene whichis subsequently treated with hydrogen peroxide by methods generallyknown in the art.

The compounds of this invention may also be prepared using a complex ofan appropriate lactam with phosphorus oxychloride, phosgene,borontrifluoride etherate, dimethyl sulfate, hydrogen halide or acombination of two or more such reagents. The complex formed is reactedwith an appropriate primary amine described hereinabove in an aromatichydrocarbon solvent such as benzene, toluene or xylene or an alkylpolyhalide solvent such as carbon tetrachloride, chloroform, methylenechloride, dichloroethane, tetrachloroethylene or the like. The reactiontemperature is limited by the boiling point of the solvent, however, insome cases it is advantageous to carry out the reaction at roomtemperature or with cooling at 0 to -40° C. depending on the reactants.

EXAMPLES

Representative compounds of the invention and their preparation as wellas pharmaceutical compositions and their preparation are illustrated inthe following specific examples.

EXAMPLE 1 Hexahydro-2-[(cis-2-phenylcyclopentyl)imino]azepinehydrochloride

A mixture of 4.0 g of cis-2-phenylcyclopentylamine hydrochloride, M.P.205°-206° C. and 5.0 ml of O-methylcaprolactim was allowed to stand atroom temperature for 6 days with occasional stirring. A few drops ofethanol were added to maintain a stirrable slurry, after which themixture was cooled. The resulting solid was washed with ether andrecrystallized from acetone/methanol to give the desired product, M.P.181.5°-183.5° C. (dec.).

EXAMPLE 2 Hexahydro-2-[(trans-2-phenylcyclopentyl)imino]azepinehydrochloride

Following the procedure of Example 1, only substituting forcis-2-phenylcyclopentylamine hydrochloride the appropriate molarequivalent amount of trans-2-phenylcyclopentylamine hydrochloride, M.P.147°-149° C., the desired product was obtained, M.P. 192°-195° C.

EXAMPLE 3 2-[(cis-2-Cyclohexylcyclopentyl)imino]hexahydroazepinehydrochloride

(A) Using rhodium-on-charcoal catalyst in a Paar shaker, 12.6 g ofcis-2-phenylcyclopentylamine hydrochloride, M.P. 204°-206° C. in 100 mlof water was hydrogenated. In 20 hours when the theoretical amount ofhydrogen had been taken up the catalyst was removed by filtration, thefiltrate made basic with sodium hydroxide solution, and the resultingprecipitate was extracted into ether. After evaporation of the ether theresidue was distilled, B.P. 100°-102° C. (6.0 mm). The hydrochloridesalt was prepared and recrystallized from isopropanolether to give 4.4 gof cis-2-(cyclohexyl)cyclopentylamine hydrochloride, M.P. 174°-176° C.

(B) By the procedure of Example 1 only employing a reaction time of 29days and substituting for cis-2-phenylcyclopentylamine hydrochloride anappropriate amount of cis-2-cyclohexylcyclopentylamine hydrochloride,the desired product was obtained, M.P. 179°-180° C.

EXAMPLE 4 2-[(trans-2-Cyclohexylcyclopentyl)imino]hexahydroazepinehydrochloride

By the procedure described in Example 3(A) only substituting forcis-2-phenylcyclopentylamine hydrochloride an appropriate amount oftrans-2-phenylcyclopentylamine hydrochloride, M.P. 142°-143° C., thehydrochloride salt of trans-2-cyclohexylcyclopentylamine was obtained,M.P. 199°-200° C. Following the procedure of Example 1 only substitutingfor cis-2-phenylcyclopentylamine hydrochloride an appropriate amount oftrans-2-cyclohexylcyclopentylamine hydrochloride and employing areaction time of 38 days, the desired product was obtained, M.P.208°-210° C.

EXAMPLE 5 2-[2-{p-Chlorophenyl}cyclopentyl)imino]hexahydroazepinehydrochloride

From 575 g of p-chlorophenyl bromide and 78 g of magnesium turnings in2.6 liters of anhydrous ether was prepared p-chlorophenyl magnesiumbromide to which was added dropwise a solution of 252 g ofcyclopentanone in 1 liter of ether. The mixture was stirred overnightand was decomposed by careful addition of dilute hydrochloric acid. Theorganic phase was separated, washed and dried, and the solvent wasevaporated. The resulting solid was recrystallized from ethanol to give316 g of 1-(p-chlorophenyl)cyclopentene, M.P. 71°-73° C., which wasdissolved in 2.9 liters of acetic acid containing 6 ml of concentratedsulfuric acid. To this solution 133 g of 50% hydrogen peroxide was addeddropwise during which time the reaction temperature was maintained at30° to 35° C. The reaction mixture was stirred overnight after whichwater was added and the product was extracted into ether. The extractwas washed, dried and the solvent evaporated leaving crude2-(p-chlorophenyl)cyclopentanone which was distilled, B.P. 135°-154° C.(0.1 mm) yielding 140 g. The oxime, M.P. 154°-155° C. was reduced usingRaney nickel in alcoholic ammonia to give2-(p-chlorophenyl)cyclopentylamine which was subsequently converted tothe hydrochloride salt, M.P. 226°-228° C. Following the procedure ofExample 1, only substituting for cis-2-phenylcyclopentylaminehydrochloride, an appropriate amount of2-(p-chlorophenyl)cyclopentylamine hydrochloride, the desired productwas obtained, M.P. 253°-255° C.

EXAMPLE 6

Following the procedure of Example 1, only substituting forO-methylcaprolactim an appropriate amount of O-methylenantholactim,O-methylcaprylolactim, O-methylvalerolactim orO-methyl-5-tert-butylcaprolactim, the following compounds are obtained:

octahydro-2-[(cis-2-phenylcyclopentyl)imino]azocine hydrochloride,

octahydro-2-[(cis-2-phenylcyclopentyl)imino]azonine hydrochloride, M.P.207°-209° C.

2-[(cis-2-phenylcyclopentyl)imino]piperidine hydrochloride, M.P.173°-176° C.,

5-tert-butylhexahydro-2-[(cis-2-phenylcyclopentyl)imino]azepinehydrochloride, M.P. 291°-293° C.

EXAMPLE 7 Hexahydro-2-[(trans-2-phenylcyclohexyl)imino]azepinehydrochloride

Following the procedure of Example 1, only substituting forcis-2-phenylcyclopentylamine hydrochloride an appropriate amount oftrans-2-phenylcyclohexylamine hydrochloride, M.P. 251°-257° C., andemploying a reaction time of 38 days, the desired product was obtained,M.P. 236°-239° C.

By the procedure of Example 1, only substituting forcis-2-phenylcyclopentylamine hydrochloride an appropriate amount of thehydrochloride salt of an amine listed in Table I, the respectiveproducts listed in Table I are obtained. The amines employed in Examples8 through 12 are described by W. F. Trager et al., in J. Org. Chem. 27,3006-10 (1962), and those used in Examples 13 and 14 are described by M.Mousseron and M. Mousseron-Canet, C. R. Acad. Sci. 239, 502 (1954). Theamines employed in Examples 15 and 16 are obtained by the reduction of2-(m-anisyl)cyclohexanone oxime and 2-(p-anisyl)cyclohexanone oxime [W.C. and R. B. Wildman, J. Org. Chem. 17, 581 (1952)] and those used inExamples 17 and 18 are obtained by the reduction of the oxime of2-cyclopentylcyclopentanone (H. Cristol et al., Bull. Soc. Chim. France1958, 556).

                  Table I                                                         ______________________________________                                        Ex-                                                                           ample                                                                         No.   Amine            Final Product                                          ______________________________________                                         8    2-o-tolyl)cyclohexylamine                                                                      hexahydro-2-[2-({o-tolyl}-                                                    cyclohexyl)imino]azepine                                9    2-(p-tolyl)cyclohexylamine                                                                     hexahydro-2-[2-({p-tolyl}-                                                    cyclohexyl)imino]azepine                                                      hydrochloride                                          10    2-(o-chlorophenyl)cyclo-                                                                       2-[2-({o-chlorophenyl}-                                      hexylamine       cyclohexyl)imino]hexa-                                                        hydroazepine hydrochloride                             11    2-(m-chlorophenyl)cyclo-                                                                       2[2-({m-chlorophenyl}-                                       hexylamine       cyclohexyl)imino]hexa-                                                        hydroazepine hydrochloride                             12    2-(p-chlorophenyl)cyclo-                                                                       2-[2-({p-chlorophenyl}-                                      hexylamine       cyclohexyl)imino]hexa-                                                        hydroazepine hydrochloride                             13    cis-2-cyclopentylcyclo-                                                                        2-[2-({cis-2-cyclopentyl}-                                   hexylamine       cyclohexyl)imino]hexa-                                                        hydroazepine hydrochloride                             14    trans-2-cyclopentylcyclo-                                                                      2-[2-({trans-2-cyclopentyl}-                                 hexylamine       cyclohexyl)imino]hexa-                                                        hydroazepine hydrochloride                             15    2-(m-anisyl)cyclohexyl-                                                                        2-[2-({m-anisyl}cyclohexyl)-                                 amine            imino]hexahydroazepine                                                        hydrochloride                                          16    2-(p-anisyl)cyclohexyl-                                                                        2-[2-({p-anisyl}cyclohexyl)-                                 amine            imino]hexahydroazepine                                                        hydrochloride                                          17    cis-2-(cyclopentyl)cyclo-                                                                      2-[2-({cis-2-cyclopentyl}-                                   pentylamine      cyclopentyl)imino]hexa-                                                       hydroazepine hydrochloride                             18    trans-2-(cyclopentyl)-                                                                         2-[2-({trans-2-cyclopentyl}-                                 cyclopentylamine cyclopentyl)imino]hexa-                                                       hydroazepine hydrochloride                             ______________________________________                                    

EXAMPLE 19 Hexahydro-2-[(2-{2-thienyl}cyclopentyl)imino]azepinehydrochloride

By the procedure described in U.S. Pat. No. 2,520,516 (1950)2-(2-thienyl)cyclopentylamine hydrochloride, M.P. 168°-172° C., wasprepared and substituted for cis-2-phenylcyclopentylamine hydrochloridein Example 1 to give the desired product, M.P. 144°-151° C.

EXAMPLE 20 cis- andtrans-Hexahydro-2-[(2-phenylcycloheptyl)imino]azepine hydrochloride

Following the procedure of Example 1 only substituting forcis-2-phenylcyclopentylamine hydrochloride an appropriate amount of cis-or trans-2-phenylcycloheptylamine hydrochloride, M.P. 229°-230° C. and199°-201° C. respectively, and using reaction times of 20 and 21 daysrespectively, the desired products were obtained, cis- M.P. 234°-235°C., trans- M.P. 207°-211° C.

EXAMPLE 21 2-[(cis-2-Cyclohexylcyclopentyl)imino]piperidinehydrochloride

Following the procedure of Example 1, only substituting forcis-2-phenylcyclopentylamine hydrochloride and O-methylcaprolactim,appropriate amounts of cis-2-(cyclohexyl)cyclopentylamine hydrochlorideand O-methylvalerolactim respectively the desired product was obtained.M.P. 195.5°-197° C.

EXAMPLE 22 2-[(cis-2-Phenylcyclopentyl)imino]azacyclotridecanehydrochloride

To 21.7 g of 2-azacyclotridecanone in 200 ml of dry benzene was addeddropwise 15.3 g of phosphorus oxychloride. The mixture was stirred atroom temperature for 4 hours after which 19.8 g ofcis-2-phenylcyclopentylamine hydrochloride was added. The reactionmixture was stirred at room temperature for 2 hours and refluxed for 24hours. The resulting homogeneous solution was washed with 2N NaOH, 2NHCl and saturated NaCl solution, dried over sodium sulfate and thesolvent evaporated. The resulting oily product crystallized from acetoneand was recrystallized from methanol-acetone to give the desiredproduct, M.P. 156°-159° C.

EXAMPLE 23

By the procedure of Example 22, only substituting for2-azacyclotridecanone an appropriate amount of N-methyl-2-pyrrolidone or3-chlorocaprolactam the following products are obtained:

N-methyl-2-[(cis-2-phenylcyclopentyl)imino]pyrrolidine hydrochloride,

3-chloro-2-[(cis-2-phenylcyclopentyl)imino]hexahydroazepinehydrochloride.

EXAMPLE 24 O-Methylvalerolactim

To a refluxing solution of 100 g of valerolactam in 350 ml of drybenzene was added dropwise 125 g of dimethylsulfate. After refluxingovernight the mixture was treated with saturated potassium carbonatesolution, dried and the solvent was evaporated. The product wasdistilled at 20 mm, B.P. 55°-57° C.

EXAMPLE 25

Following the procedure of Example 24 only substituting for valerolactaman appropriate amount of enantholactam, caprylolactam,5-tert-butylcaprolactam or caprolactam the following compounds wereprepared:

O-methylenantholactim, B.P. 48°-53° C. (2.0 mm),

O-methylcaprylolactim, B.P. 44°-46° C. (0.5 mm),

O-methyl-5-tert-butylcaprolactim, B.P. 76°-79° C. (0.4-2.3 mm),

O-methylcaprolactim, B.P. 60°-65° C. (13.0 mm).

EXAMPLE 26 2-(Hexahydroazepin-2-ylidenamino)-1-phenylcyclopentanolhydrochloride

A solution of 73.5 g (0.75 mole) of 1,2-cyclopentanedione in 400 ml ofether was added to 1.5 moles of phenyl lithium in 1.2 liter of ether,and the mixture was stirred under N₂ for one half hour. After carefuladdition of water, the ethereal layer was separated, dried overmagnesium sulfate and the solvent evaporated. The residue was distilledunder reduced pressure and gave 77.2 g of2-hydroxy-2-phenylcyclopentanone, b.p. 122°-126° C. (1.5 mm), n_(D) ²⁵1.5551. The oxime was prepared by known procedures, m.p. 110°-112° C.,and was reduced by hydrogenation over Raney nickel in 20% alcoholicammonia. Removal of catalyst, evaporation of solvent and addition of HClgave 2-hydroxy-2-phenylcyclopentylamine hydrochloride, m.p. 198°-199° C.

Following the procedure described in Example 1, only substituting forcis-2-phenylcyclopentylamine hydrochloride an appropriate amount of2-hydroxy-2-phenylcyclopentylamine hydrochloride and employing areaction time of 47 days the desired product was obtained, M.P.261°-262° C.

EXAMPLE 27 5-Methyl-2-[(2-phenylcyclopentyl)imino]pyrrolidinehydrochloride

A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylaminehydrochloride and 3 ml of 5,O-dimethylbutyrolactim is allowed to standat room temperature for 6 days with occasional stirring during whichtime sufficient ethanol is added to maintain the slurry. The slurry isthen cooled to -20° C., and after about 4 hours a precipitate forms. Theprecipitate is collected and recrystallized several times fromacetone-methanol to give5-methyl-2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P.175°-178° C.

EXAMPLE 28 2-[(2-Phenylcyclopentyl)imino]pyrrolidine hydrochloride

A slurry of 3.0 g (0.0152 mole) of powdered 2-phenylcyclopentylaminehydrochloride and 3 ml of O-methylbutyrolactim is allowed to stand atroom temperature with occasional stirring for 6 days after which thematerial is covered with absolute ether. The solution is allowed tostand at room temperature for an additional 6 days. A precipitate formswhich is collected and recrystallized from acetone-methanol and dried togive 2-[(2-phenylcyclopentyl)imino]pyrrolidine hydrochloride, M.P.155°-158° C.

EXAMPLE 29 5-Methyl-2-[(cis-2-cyclohexylcyclopent-1-yl)imino]pyrrolidinehydrochloride

When in the procedure of Example 27, 3.0 g (0.0147 mole) of1-cyclohexylcyclopentylamine hydrochloride is substituted for1-phenylcyclopentylamine, and the slurry is allowed to stand at roomtemperature for 8 days,5-methyl-2-[(cis-2-cyclohexylcyclopent-1-yl)imino]pyrrolidinehydrochloride is obtained, M.P. 234°-236° C. (dec).

EXAMPLE 30 2-[(cis-2-cyclohexylcyclopent-1-yl)imino]pyrrolidinehydrochloride

A slurry of 3.0 g (0.0147 mole) of powdered 1-cyclohexylcyclopentylaminehydrochloride and 3 ml of O-methylbutyrolactim is allowed to stand atroom temperature for 8 days during which time sufficient ethanol isadded to maintain a slurry. A precipitate forms which is collected,washed with ether, dried and recrystallized from acetone-methanol togive 2-[(cis-2-cyclohexylcyclopent-1-yl)imino]pyrrolidine hydrochloride,M.P. 227°-228° C.

EXAMPLE 31 1-Benzyl-2-[(cis-2-phenylcyclopentyl)imino]pyrrolidinehydrochloride

To 26.3 g (0.15 mole) of N-benzylbutyrolactone in 200 ml of dry benzeneis added dropwise 19.2 g (0.125 mole) of phosphorus oxychloride. Themixture is stirred at room temperature for 4 hours after which 24.7 g(0.125 mole) of 1-phenylcyclopentylamine hydrochloride is added, andstirring is continued at room temperature for 2 hours. The reactionmixture is refluxed for 24 hours and then allowed to stand at roomtemperature for five days. A solid forms which is separated and thefiltrate is washed with 2N HCl. The wash and solid residue are madebasic with 2N sodium hydroxide solution, extracted into ether and driedover sodium sulfate to give 40.3 g of an oil. To the oil in acetone isadded one equivalent of methanolic HCl. A precipitate forms which isrecrystallized from methylene chloride-ether to give1-benzyl-2-[(cis-2-phenylcyclopentyl)imino]pyrrolidine hydrochloride,M.P. 158°-166° C.

EXAMPLE 32

An illustrative composition for tablets is as follows:

    ______________________________________                                                               Per Tablet                                             ______________________________________                                        (a)   2-[(2-cyclohexylcyclopentyl)imino]-                                           hexahydroazepine hydrochloride                                                                        100 mg                                          (b)   Wheat starch            15 mg                                           (c)   Lactose                33.5 mg                                          (d)   Magnesium stearate      1.5 mg                                          ______________________________________                                    

A granulation obtained upon mixing lactose with the starch andgranulated starch paste is dried, screened and mixed with the activeingredient and magnesium stearate. The mixture is compressed in tabletsweighing 150 mg each.

In a similar manner other compositions may be prepared by substitutingthe other compounds of this invention for2-[(2-cyclohexylcyclopentyl)imino]hexahydroazepine used in this example.

We claim:
 1. A compound selected from(A) a compound of the formula##STR8## (B) a pharmaceutically acceptable acid addition salt thereof,wherein Y is thienyl; Z is hydrogen or hydroxy; R is selected from thegroup consisting of hydrogen, lower alkyl of from 1 to 4 carbon atoms,phenyl or benzyl; R¹ is selected from the group consisting of hydrogen,halogen or lower alkyl of from 1 to 4 carbon atoms; m is an integer offrom 3 to 6; and n is an integer of from 3 to
 11. 2. A compound of claim1 where m is 3 to 5, n is 4 to 7 and R and R¹ are each hydrogen.
 3. Acompound of claim 2 where Z is hydrogen.
 4. A compound of claim 3 whichis hexahydro-2-[(2-{2-thienyl}cyclopentyl)imino]azepine or apharmaceutically acceptable acid addition salt thereof.